Container and method for high volume treatment of samples on solid supports

ABSTRACT

A sample/collection container includes a plurality of wells, each for separating a sample from its solid support when solvent is dispensed into the wells and the centrifuge is activated at a low speed. Operation of the centrifuge at high speed concentrates the cleaved sample in collection wells.

RELATED APPLICATIONS

This application is related to applications Ser. No. 09/549,958,entitled SYSTEM AND METHOD FOR TREATMENT OF SAMPLES ON SOLID SUPPORTS,and Ser. No. 09/549,283, SYSTEM AND METHOD FOR DISPENSING SOLUTION TO AMULTI-WELL CONTAINER, each having the same filing date as, and assignedto the assignee of, the present application.

FIELD OF THE INVENTION

The invention relates to a system and method for automated treatment ofchemical compounds or biological materials on solid supports, and morespecifically, a system and method for automated purification, elution,cleavage, transfer, concentration and/or evaporation of biological orchemical samples on solid supports.

BACKGROUND OF THE INVENTION

In recent years, the pharmaceuticals industry has devoted significantresources to finding ways to cut the time required for identificationand validation of lead drug candidates. Disciplines that have arisen toaddress this need include high-throughput screening and combinatorialchemistry. Using combinatorial methods, libraries made up of largenumbers of compounds are randomly or semi-randomly synthesized, thenevaluated using high-throughput screening, looking for biologicalactivity or chemical reactions. The availability of solid-phasesupports, e.g., resin beads, balls, disks or tubes, for organicsynthesis has contributed significantly to the ability to create largecombinatorial libraries, making it possible to synthesize a uniquecompound on each support. Encoding of the solid support enablesindividual labeling of each compound and tracking of the compound'sreaction history. Examples of tagging and tracking techniques asdescribed in U.S. Pat. Nos. 5,770,455 and 5,961,923, both assigned tothe assignee of the present application, the disclosures of which areincorporated herein by reference. Such tagging and/or trackingcapabilities permit discrete compound split-and-pool synthesis, allowingthousands to millions of compounds to be generated at a time whilekeeping track of the history of each uniquely synthesized compoundthroughout the synthesis and subsequent cleaving operations. However,while synthesis and tracking are facilitated by solid phase methods,analysis of the compound or its intermediates may, for many testsrequires removal of the synthesized compounds from their solid phasecarriers, such that individualized cleavage and concentration of eachcompound becomes essential. Furthermore, for generation of commerciallibraries, it would be preferable to provide the compounds in aconvenient form that would require the purchaser to do minimaladditional processing in order to perform subsequent assays or otheranalyses, i.e., following cleaving from the solid support andconcentration of the compound. Thus, automated cleavage, concentrationand collection of the compounds in a manner that significantly reducesthe bottleneck in an otherwise high-throughput process, which allows thecompounds to be readily tracked, and which avoids loss of material orcross-contamination between compounds, is an important step in achievingthe goals of rapid drug discovery and development.

Solid phase methods have similarly been applied for analysis ofbiological compounds. Generally, solid phase oligonucleotide synthesisinvolves covalently attaching the base building block to a solid supportsuch as controlled pore glass (CPG), polystyrene-copolymer, polyester,silica gel, polyamide/Kieselguhr, charged nylon, glass fiber,nitrocellulose or cellulose paper, then synthesizing the oligonucleotideby placing the solid support in a reaction vessel with excess protectednucleosides and coupling reagents.

After completion, the oligonucleotide is cleaved from the solid supportthen deprotected, after which the appropriate analysis can be performed.Such methods have been adapted for purification of DNA, which typicallyinvolves the selective elution of impurities by exposing the biologicalsample to a number of reagents and incubating at elevated temperatures.The sample remains attached to the solid support throughout thepurification steps then, if desired, the sample can be cleaved from thesolid support. DNA purification procedures often require a combinationof hazardous reagents, physical force (centrifuge, air pressure orvacuum), lengthy incubation periods and high temperatures (100° C.),which can require special containers and equipment that may not be wellsuited for very high throughput operations. For example, seeInternational Patent Application No. WO99/13976 of Gentra Systems, Inc.,which discloses an automated apparatus for isolating DNA, in whichbiological samples are combined with solid supports in a sampleprocessing container, wash solution is dispensed into the containers anddrained a number of times, then the sample containers are loaded onto apurification apparatus, e.g., a centrifuge. After completion of thepurification step, the sample processing container is removed and movedto the next station for cleavage (elution) of the purified sample fromthe solid support. Thus, while the method disclosed in the referencedPCT application is automated, there is still a significant amount ofhandling and moving of the samples and sample containers required tocomplete the purification and elution process.

Systems are known for performing cleavage, elution, concentration,purification, and/or collection of multiple samples, both chemical andbiological, however, such systems are not easily integrated into asingle processing system that enables the handling of a large number ofsamples to be cleaved, concentrated and collected automatically. Forexample, the centrifugal system for vacuum concentration of biologicalspecimens disclosed in U.S. Pat. No. 5,334,130 enables treatment ofmultiple biological samples within the centrifuge chamber. Cleavage ofthe compounds from their supports is effected by pouring a typicallycaustic cleaving agent into each vial before placing the vials into thecentrifuge chamber. The chamber is sealed and heated to acceleratecleavage. After cleavage is complete, the concentration step occursduring which the chamber is evacuated and the centrifuge rotor isactivated to evaporate the cleaving agent. The rotor speed can sometimesbe selected to minimize “bumping”, which can cause solid or liquid formmaterial to be propelled out of the vial due to violent outgassingcaused by boiling of the solvent. In the system disclosed in the '130patent, the rotor has a number of holder positions, each of whichincludes a pressure relief valve for its corresponding vial, thuslimiting the number of sample-containers, and consequently, the numberof samples, to the number of holder position.

An important aspect of streamlining the process for synthesis, cleavageand concentration of compounds involves establishing a system thatallows the compounds to be processed through multiple process stepswithout frequent transfer of the solid supports and/or compounds fromone container to another as needed to allow a certain piece of equipmentto be used. However, in the described systems, unless prior processingsteps were also performed in the sample containers, transfer into suchcontainers would be required before the cleavage and concentrationprocedure could be performed. Thus, the cleavage/concentration stepswould become rate-limiting in a high-throughput process for severalreasons which include: (1) additional handling of the samples isrequired to place them in the containers; (2) the often-hazardouscleavage agent must be introduced into the container, then the containercarefully carried to the centrifuge chamber for loading; and (3) thecleavage and concentration steps are performed as separate procedures.

For the reasons described above, there remains a need for a system forprocessing of samples on solid supports, which may include cleavage,transfer/collection and/or concentration, that allows for a highlyautomated method of reagent delivery, cleaving, transfer and/orconcentration of a large number of chemical or biological samples in arapid, cost effective manner.

SUMMARY OF THE INVENTION

It is an advantage of the present invention to provide a system thatautomatically dispenses one or more liquid solutions within a centrifugefor simultaneous treatment of a number of chemical or biological sampleson solid supports.

It is another advantage of the present invention to provide a system andmethod for automatically sample washing, eluting, cleaving,concentrating and collecting a large number of samples on solidsupports.

Still another advantage of the present invention is to permit treatmentof chemical or biological samples in a sealed system which avoids theneed for operator handling of hazardous solutions and permits a vacuumto be applied during processing.

It is a further advantage of the present invention to provide anautomated system and method for processing of chemical or biologicalsamples that allows the processing temperature to be accuratelycontrolled to prevent heat damage to samples and containers.

Another advantage of the present invention is to provide an automatedsystem that significantly minimizes the possibility ofcross-contamination and/or loss of samples during processing.

Yet another advantage of the present invention is to provide anautomated system that precisely measures and dispenses hazardoussolutions during all processing operations in a sealed system.

In an exemplary embodiment, the automated processing system of thepresent invention comprises a computer-based control unit and a mainunit comprising a variable-speed centrifuge having an openablevacuum-tight chamber and a centrifuge rotor with a plurality ofmulti-sample holding positions, a liquid solution supply subsystem whichfeeds solvent or other solution to a plurality of dispensing stations inthe centrifuge chamber, a temperature control subsystem, and a vacuumsubsystem. In the preferred embodiment bar code reader or otheridentification means, preferably a non-contact reader, can be includedin the chamber to allow sample carriers to be identified.

Solid support-bound sample compounds are retained within a multi-wellsample container which is mated on its lower end with a collectioncontainer possessing a collection well corresponding to each well of thesample container. When mated, the two containers are inserted into oneof the multi-sample holding positions on the centrifuge rotor. Afterclosing the centrifuge chamber, cleaving solvent (or other appropriatereagent) is automatically dispensed into each well of the samplecontainer, with the centrifuge rotor being rotated to position eachsample container at the dispensing station. By running the rotor at alow rotational speed while dispensing and during cleavage, potentialcarryover of solvent and/or samples (“creep”) between the wells issignificantly minimized. As the rotor turns, samples are allowed toincubate until the samples are cleaved from the solid supports. Whencleaving is complete as pre-programmed based upon the sample types and,for chemical compounds, the linker types, the rotor speed is increased,causing the cleaved sample and solvent to be transferred to thecollection container, leaving the solid support in the sample container.After all of the cleaved solutions are transferred into the collectioncontainers, the rotor speed is increased to a relatively high rate. Thecollection containers are uniformly heated, causing the cleaving solventto uniformly evaporate at a user-programmable rate. The vacuum withinthe chamber is controlled to accelerate the evaporation. After apre-determined period of time, the process is terminated, leaving theconcentrated samples in the bottoms of the wells of the collectioncontainers.

In the preferred embodiment, the control unit comprises a PC with aWindows®-type operating system to provide a user-interface via mouse orkeyboard. The PC includes a memory within which is stored software forcontrolling and monitoring the various subsystems within thecleavage/evaporation system. Where the cleavage/evaporation system ispart of a processing system for synthesizing compounds, the memory willalso preferably have stored therein software for management of thesynthesis, including tracking of the encoded solid supports, thechemical building blocks used in the synthesis, and the concentratedsample compounds after cleavage. The control unit also includes powersupplies, the main control relay, and a network bus controller. Thepower supplies provide power to the main unit and any operating devicewithin the system that requires power for operation. The control unitincludes a single connection to the main electrical supply, i.e.,electrical outlet, thus providing for total system control through thecontrol unit, allowing rapid shutdown of an individual subsystem, or theentire system, if required. The main switching unit provides switchingof the devices of the main unit in response to commands issued by the PCaccording to the control software. The network bus controller providesdata transfer (I/O) between the PC and the main unit for conveyingcontrol commands to the various devices and for receiving monitoringdata from the system sensors. A conventional cable provides physicalconnection between the control unit and the main unit.

The centrifuge chamber must be sufficiently sealed so that it is capableof maintaining a vacuum and is resistant to the harsh chemicals usedduring processing of the samples. In the preferred embodiment, sampleholder positions are fixed on the centrifuge rotor, with a plurality ofinwardly-sloping support frames or blocks radially mounted atevenly-spaced positions around the rotor. In an alternate embodiment,the sample holders are pivotally mounted to swing at an increasing angleas the rotor speed increased. Each support frame is adapted to receivethe assembled combination of the sample container and collectioncontainer. The rotor has openings therethrough at locationscorresponding to each support frame to permit heating of the collectioncontainer from below the rotor. The centrifuge chamber has a pluralityof heat-transmissive windows formed in its bottom side. At least onelight-transmissive window is formed in the side of the centrifugechamber to provide access for optical reading of bar codes on the sampleand collection containers. A second light-transmissive window may beformed in the top of the centrifuge chamber to permit opticaltransmission of a signal from a temperature sensor located inside thechamber.

The solvent supply subsystem includes at least one source container andpump which provide solvent to a dispensing station. In the preferredembodiment, two dispensing stations are included, each having its ownsource container and pump, so that two different solvents can besupplied. The dispensing station includes a dispensing head which ismounted on and extends into the centrifuge chamber in a manner whichprovides access to all wells in the sample container. The dispensinghead has one dispensing tip or nipple corresponding to each well in thesample container and is arranged such that alignment of the dispensinghead with the sample container causes each dispensing nipple to alignwith its corresponding well. Each dispensing tip is connected by a tubeto a corresponding solvent reservoir in the dispenser housing. Thesolvent reservoir contains a pre-measured amount of solvent so that theprecise amount of solvent used is known. The source supply subsystemalso includes a waste reservoir for safe storage of used solvent and agas source for purging the dispenser tubing and dispensing tip.

The temperature control subsystem includes temperature sensors andheating means. Heat to the samples is supplied via infrared heat lampspositioned outside of the bottom of the centrifuge chamber at theheat-transmissive windows. Conduction and uniform dispersion of the heatentering the windows is provided by heat-conducting plates disposedwithin the support frames on the rotor, beneath each of the collectioncontainers. A thermal sensor in contact with one of the heat-conductingplates provides a signal to an optical (IR) transmitter located belowthe light-transmissive window in the top of the centrifuge chamber. Theinfrared signal is detected by a detector positioned outside of thelight-transmissive window and a signal is generated to provide feedbackto the sample heat controller for controlling the heat lamps. Additionalheat to the chamber is provided by resistive heaters mounted on thecentrifuge housing, preferably on both the top and bottom of thechamber. A sensor mounted on the outside of the chamber providesfeedback for controlling the chamber temperature.

The vacuum subsystem includes a vacuum controller for controlling a pairof pumps, which in the preferred embodiment are a Roots pump and adiaphragm pump. A condenser may be included for removal of vaporizedsolvent from the evacuated air from the centrifuge chamber to preventpossible release of the solvent into the environment.

Tracking of the location of the sample compounds is enabled byidentification of the sample and collection containers. In the preferredembodiment, each of the containers is marked with an optically-readablebar code. Orientation keys are included on the containers to ensure thatthe bar code is visible through the window in the side of the centrifugechamber. The bar code reader reads the encoded identification andprovides that information to the control unit (PC) which stores theinformation in association with the synthesis histories of the samplesas provided by the synthesis management software. The samples in thesample and collection containers are tracked spatially, according to thecoordinates of the wells in which they are placed. As an alternative tothe optical bar code, radio frequency (RF), or other remotely-readabletags may be embedded in the containers to provide means for identifyingand tracking the containers.

BRIEF DESCRIPTION OF THE DRAWINGS

Understanding of the present invention will be facilitated byconsideration of the following detailed description of a preferredembodiment of the present invention taken in conjunction with theaccompanying drawings, in which like numerals refer to like parts and inwhich:

FIG. 1 is a schematic diagram of the cleavage/evaporation system of thepresent invention;

FIG. 2 is a perspective view of the basic system including thecentrifuge;

FIG. 3 is a top plan view of the system;

FIG. 4 is a sectional view taken along line 4—4 of FIG. 3;

FIG. 5 is a diagram of the bearing purging subsystem;

FIG. 6 is a top plan view of the centrifuge with the cover removed;

FIG. 7 is a perspective view of a portion of the centrifuge rotorshowing the container holders;

FIG. 8 is an enlarged front view of the cover latching mechanism;

FIG. 9 is a sectional view taken along line 9—9 of FIG. 8;

FIG. 10 is similar to a portion of FIG. 9, showing the cover unlatched;

FIG. 11 is a diagram of the container heating system;

FIG. 12 is a diagram of the chamber heating subsystem;

FIG. 13 is a diagram of the solution dispensing subsystem;

FIG. 14 is a perspective view of a solution dispensing head;

FIG. 15 is a view similar to that of FIG. 14, with the top coverportions removed;

FIG. 16 is a view similar to that of FIG. 14 showing the compoundcontainer;

FIG. 17 is a perspective view of the compound container;

FIG. 18 is a side view of the dispensing unit showing the motion of thehead;

FIG. 19 is a front view of the dispensing unit showing the headactuating mechanism;

FIG. 20 is a top plan view of the sample container;

FIG. 21 is an enlarged sectional view taken along line 21—21 of FIG. 20;

FIG. 22 is a side view of the sample container, with the attachedcollection container shown in broken line;

FIG. 23 is a top plan view of the collection container;

FIG. 24 is a sectional view taken along line 24—24 of FIG. 23;

FIG. 25 is a diagrammatic view of a well of a first embodiment of thesample container;

FIG. 26 is a sectional view taken along line 26—26 of FIG. 25;

FIG. 27 is a top plan view of the reservoir fill container; FIG. 28 is asectional view taken along line 28—28 of FIG. 27;

FIG. 29 is a bottom plan view of the reservoir fill container;

FIG. 30 is a side view, partially cut away, of a transferlesssample/collection container assembly; and

FIG. 31 is an exploded side view, partially cut away, of asample/collection container assembly for use in DNA purification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As illustrated in FIG. 1, the automated cleavage/evaporation system ofthe present invention comprises number of electromechanical subsystemsand mechanical structures including: a computer-based control unit 102and a main unit 104 containing a centrifuge 110 having an openablevacuum-tight chamber 112 and a centrifuge rotor 114 with a plurality ofmulti-sample holding positions, a supply subsystem 120, which includes aplurality of dispensing stations 122 (only one is shown) in thecentrifuge chamber 112, a heating/temperature control subsystem 130, avacuum subsystem 140, a bar code reader 150, waste disposal system 160,and vapor venting system 170.

For purposes of the following detailed description, the invention willbe described as used for processing, i.e., cleavage/concentration, ofsynthesized chemical compounds. Adaptation of the inventive system foruse in processing of biological samples, such as DNA purification, willbe readily apparent to those of skill in the art in view of the detaileddescription.

The resin-bound sample compounds are retained within a multi-well samplecompound container (shown in FIGS. 17 and 20-22) which is mated at itslower end with a collection container (shown in FIGS. 23 and 24)possessing a collection well corresponding to each well of the compoundcontainer. In the preferred embodiment, the sample and collectioncontainers are 96-well plates, generally corresponding to standard96-well microtiter plates, however, other container arrangements andwell configurations can be used. When mated, the two containers areinserted into one of the multi-sample holding positions on thecentrifuge rotor 114. After closing the centrifuge chamber 112, cleavingsolvent is automatically dispensed into each well of the compoundcontainer, with the centrifuge rotor 114 being rotated to position eachcompound container at the dispensing station 122. By running the rotorat a low rotational speed, e.g., at around 20-30 r.p.m., whiledispensing and during cleavage, potential carryover of solvent and/orcompounds (“creep”) between the wells is minimized. As the rotor turns,samples are allowed to incubate until the compounds are cleaved from thesolid supports. When cleaving is complete, as determined based upon thecompound and linker types, the rotor speed is increased, causing thecleaved compound and solvent to be transferred to the collectioncontainer 406, leaving the solid support in the compound container.After all of the cleaved solutions are transferred into the collectioncontainers, the rotor speed is increased. The collection containers areuniformly heated using adaptive heating subsystem 130, causing thecleaving solvent to evaporate uniformly. The vacuum subsystem 140maintains a vacuum within the chamber to accelerate the cleavage andconcentration of the samples. After a pre-determined period of time, theprocess is terminated, leaving the concentrated sample compounds in thebottoms of the wells of the collection containers.

In the preferred embodiment, the control unit comprises a PC 104 with aconventional operating system to provide a user-interface via mouse orkeyboard 108. The PC 104 includes a memory within which is storedsoftware for controlling and monitoring the various subsystems withinthe cleavage/evaporation system. Where the cleavage/evaporation systemis part of a processing system for synthesizing compounds, the memorywill also preferably have stored therein software for management of thesynthesis, including tracking of the encoded solid supports, thechemical building blocks used in the synthesis, and the concentratedsample compounds after cleavage. Control unit 102 also includes powersupplies, the main control relay, and a network bus controller. Thepower supplies provide power to the main unit and any operating devicewithin the system that requires power for operation. Control unit 102preferably includes a single connection to the main electrical supply,i.e., electrical outlet, thus providing for total system control throughthe control unit, allowing rapid shutdown of an individual subsystem, orthe entire system, if required. The main control relay providesswitching of the devices of the main unit in response to commands issuedby the PC 104 according to the control software. The network buscontroller provides data transfer (I/O) between the PC 104 and the mainunit 100 for conveying control commands to the various devices and forreceiving monitoring data from the system sensors. An umbilical cable107 provides physical connection between the control unit and the mainunit. Control unit 102 can be mounted on a computer cart 106 or otherappropriate frame to facilitate operation and maintenance.

Centrifuge chamber 112 must be sufficiently sealed so that it is capableof maintaining a vacuum and resistant to the harsh chemicals used duringprocessing of the samples. Chamber lid 116 provides access to theinterior of chamber 112 for loading and unloading of the sample andcollection containers. In the preferred embodiment, centrifuge rotor 114is fixed, with a plurality of inwardly-sloping support frames 402 orblocks mounted at evenly-spaced positions around the circumference ofthe rotor, as illustrated in FIG. 4. Each support frame 402 is adaptedto receive the assembled combination of the sample container 404 andcollection container 406. The rotor 114 has openings 702 therethrough atlocations corresponding to each support frame to permit heating of thecollection container from below the rotor, as shown in FIG. 7. Referringagain to FIG. 1, centrifuge chamber 112 has a plurality ofheat-transmissive windows 132 formed in its bottom side. At least onelight-transmissive window 152 is formed in the side of centrifugechamber 112 to provide access for optical reading of bar codes on thesample and collection containers. A second light-transmissive window 134may be formed in the top of centrifuge chamber 112 to permit opticaltransmission of a signal from a thermal sensor 1102 located inside thechamber.

The solvent supply subsystem 120 includes at least one source container124 and pump 126 which provide solvent to dispensing station 122. In thepreferred embodiment, two dispensing stations 122 are included, eachhaving its own source container 124 and pump 126, so that two differentsolvents can be supplied. Dispensing station 122 includes a dispensinghead 410 which is mounted on and extends into centrifuge chamber 112 ina manner which provides access to all wells in the sample containers.The dispensing head 410 has one dispensing nipple or tip 412corresponding to each well in the sample container 404 and is arrangedsuch that alignment of the dispensing head 410 with the sample container404 causes each dispensing tip 412 to align with its corresponding well.Each dispensing tip 412 is connected by a tube 414 to a correspondingsolvent reservoir 416 in the dispenser housing 418. The dispensing tip412 may actually be the end of the tube 414 itself, where end of thetube is inserted through bores in the dispensing head to define tip 412,as described below in more detail. Each solvent reservoir 416 contains apre-measured amount of solvent so that the precise amount of solventused is known. The source supply subsystem 120 is connected to wastecollection system 160 which includes waste reservoir 162 for safestorage of used solvent and to a gas source 129 for purging thedispenser tubing and tips.

Temperature control subsystem 130 includes temperature sensors andheating means. Heat to the samples is supplied via infrared heat lamps138 positioned outside of the bottom of centrifuge chamber 112 at theheat-transmissive windows 132. Conduction and uniform dispersion of theheat entering the windows is provided by heat-conducting plates 704disposed within support frames 402 on the rotor, beneath each of thecollection containers. (See FIG. 7.) As shown in FIG. 11, thermal sensor1102, which is attached to support frame 402 and in contact with one ofthe heat-conducting plates, provides a signal to an optical (IR)transmitter 135 located below the light-transmissive window 134 in thetop of centrifuge chamber 112. The infrared signal is detected bydetector 136 positioned outside of light-transmissive window 134 and asignal is generated to provide feedback to the sample heat controller1104 , and control unit 102, for adaptively controlling the heat lamps138 so as to prevent overshoot of the temperature at the heat plates.Additional heat to the chamber is provided by resistive heaters 1202mounted on the centrifuge housing, preferably on both the top and bottomof the chamber, as shown in FIG. 12. One or more sensors 1204 mounted onthe outside of the chamber provides feedback to the chamber temperaturecontroller 1206 for controlling the chamber temperature.

Referring again to FIG. 1, vacuum subsystem 140 includes a vacuumcontroller 142 for controlling a pair of pumps, which in the preferredembodiment are a Roots blower-type pump 144 and a diaphragm pump 146. Achilled water condenser 148 may be included in-line with diaphragm pump146 to remove vaporized solvent from the evacuated air from thecentrifuge chamber to prevent possible release of the solvent into theatmosphere.

Vapor venting subsystem 170 is connected to and driven by the user'slaboratory exhaust vent and draws vapor from the cabinet containing thesource container 124, the area under centrifuge 110, the area around thecentrifuge access door 116, and the cabinet housing the waste container162.

Tracking of the location of the sample compounds is enabled byidentification of the sample and collection containers using theidentification subsystem. In the preferred embodiment, each of thecontainers is marked with an optically-readable bar code. Orientationkeys are included on the containers to ensure that they are positionedon the rotor so that the bar code is visible through window 152 in theside of the centrifuge chamber 112. The bar code reader 150 reads theencoded identification on each container and provides the identificationinformation to the control unit 102 (PC 104) which stores theinformation in association with the synthesis histories of the compoundsas provided by the synthesis management software. The identities of thecompounds in the sample and collection containers are tracked spatially,according to the coordinates of the wells in which they are placed. Asan alternative to the optical bar code, radio frequency (RF), or otherremotely-readable tags may be partially or completely embedded in orattached to a surface of the containers to provide means for identifyingand tracking the containers. For example, RF tags, (transponders) wouldbe embedded in the containers at a location that faces radially outwardwhen the containers are placed in the loading positions of thecentrifuge rotor. The bar code reader would then be replaced with ascanner that in an RF transmitter/receiver which transmits an inquirysignal to the RF tag and reads the response containing data indicativeof the container identity.

The following discussions provide additional details of the structureand operation of each unit and key subsystems and components within thecleavage/evaporation system of the present invention:

Control Unit 102:

Control unit 102 monitors and controls all operations and equipmentdevices of the cleavage/evaporation system. The control unit 102, shownin FIG. 1, comprises a control unit rack 106, a control computer, which,in the preferred embodiment is a PC 104, a user interface 108, and acontrol network 109. Control network 109 is illustrated in FIG. 1 as awire-based system, connected to the main unit 100 via an umbilical 107.However, communication can also be provided by a wireless system, usingRF, optical, or other transmitted signals for communication. Controlunit rack 106 can be a conventional electronic equipment or computerrack with one or more shelves to support equipment. The control unitrack 106 will preferably be mounted on wheels to facilitate mobility inoperation and maintenance of the cleavage/evaporation system.

PC 104 provides the primary functions of monitoring and controllingoperations of the different components of the cleavage/evaporationsystem according to instructions generated by control network softwarewhich are communicated via control network 109.

The software which controls the operation of the cleavage/evaporationsystem includes an operating system, such as WindowsNT® or Windows®-typesystems, and control network software which is adapted to interface withor work off of the operating system. The control network software can beany software that interfaces with the control network and providescommunication between PC 104 and the main unit 100, allowing PC 104 tomonitor and control devices attached to the control network. In thepreferred embodiment, Visual Basic™ software is used to control thesystem through a DeviceNet™ interface card installed in PC 104.Appropriate interface cards are widely available from a number ofmanufacturers of electronics for automation systems. NationalInstruments is one source of such interface cards.

Generally, control network 109 is a CAN (Controller Area Network), awidely-used protocol for automation applications. CAN is abroadcast-oriented, communications protocol which defines the means bywhich data transmission occurs, providing fast response and highreliability. In the preferred embodiment, control network 109 comprisesa fieldbus system operating using the DeviceNet™ communication link anda plurality of I/O (input/output) modules which are connected to andcommunicate with the devices in the main unit 100. A fieldbus, which isgenerally known in the art, is an all-digital, serial, two-waycommunications system that interconnects measurement and controlequipment such as sensors, actuators and controllers. The fieldbusserves a function similar to that of a Local Area Network (LAN) forinstruments used in process control, remote I/O and manufacturingautomation applications and has a built-in capability to distribute thecontrol application across the network.

The DeviceNet™ communication link, which is based on the CAN protocol,describes the application layer. The DeviceNet™ protocol is objectoriented. The DeviceNet™ specification is available from Open DeviceNetVendor Association, Inc. (ODVA). Implementation of the DeviceNet™ linkcan be achieved using I/O devices such as the WAGO I/O System, availablefrom WAGON Corporation (Germantown, Wis.), to construct a plurality offieldbus nodes, each comprising a fieldbus coupler, a number of specialfunction modules, or control adapters, and a termination module. Othersources of appropriate components and systems for implementing theDeviceNet™ link include Allen Bradley I/O from Rockwell Automation andSST from Woodhead Connectivity (Waterloo, Ontario, Canada).

Under DeviceNet™, each network node is identified by a Media AccessIdentifier (MAC ID), which range in value from 0 to 63. Each networknode can connect a plurality of network devices to the network. Thecontrol adapters allocate a unique I/O (input/output) address or objectaddress to each separate device in the main unit, thus permitting directaccess to each device.

Each signal name describes the state or process that will be true oractive when that signal is true as perceived by the PC's control programthe relationship between the logical polarity (true/false state) of asignal and the voltage and current in an associated wire is as follows:

Outputs are similarly arranged in that an output signal is made “true”by the control program in the PC when the output circuit is connected toground. A “false” output signal generated by the control program willresult in an open circuit at the output terminal. For example, if asolenoid has one wire connected to +24 V and the other to the outputterminal, when the control program sends a “true” signal, current willflow through the solenoid so that the solenoid is activated.

Alternatively or in addition to the DeviceNet™ network, a programmablelogic controller (PLC) may be included as part of control network 109 toprovide an interface between the control computer and the controlleddevices, e.g., to generate drive signals to activate solenoids, relaysand switches required to operate the devices. PLCs are well known andwidely used. Selection of an appropriate PLC and the logic forsupporting its operation will be apparent to those of skill in the art.

In the preferred embodiment, software stored within PC 104 also includesprogramming for directing compound synthesis and handling of the solidsupports and the compounds synthesized thereon. Using such software, PC104 is capable of tracking each of the synthesized compounds from startto finish, making a record of the synthesis history and ultimatedestination of the synthesized compounds. An example of such software isSYNTHESIS MANAGER™, which is commercially available from IRORI (SanDiego, Calif.). A description of key components of this software isprovided in co-pending application Ser. No. 08/958,254, filed Oct. 7,1997, incorporated herein by reference, which application is assigned tothe assignee of the present application.

To provide a brief description of operation of exemplary synthesismanagement software, in the first step of a process for building acombinatorial library, the individual building blocks, i.e., monomers,nucleotides or amino acids or other small molecules, and the steps inwhich they are to be used are defined. The software performs operationsfor automatically creating a data base record within the PC's memory foreach compound to be synthesized. Pre-reaction procedures, reactionconditions, and work-up procedures are also stored for each step. Theuser selects the synthesis procedure and the synthesis managementsoftware generates a display of the procedure for review by the user,then reads each of the memories associated with each solid support andsorts them for the next reaction step. When the sorting is complete, thereaction condition information and work-up procedure can be displayed tothe user.

When the synthesis is complete, the solid supports and their attachedsynthesized compounds are washed, then transferred into a multi-wellsample container, such as a 96-well plate, preferably using an automatedloader which is in communication with PC 104. During loading, theautomated loader provides a record of the location of the well in theplate into which each compound is loaded which is stored in the databasecontaining the synthesis history for that compound. Typically, therecord will consist of a pair of coordinates, i.e., x,y coordinates, touniquely identify each well in the plate.

After loading the sample and collection containers, the synthesismanagement software directs the cleavage/evaporation system to cleavethe compounds from the solid supports and concentrate the compounds inthe collection containers. The bar code reader of thecleavage/evaporation system provides input for creating a record linkingthe sample container with its associated collection container. Thus, thecompounds are tracked to their final destination in the collectioncontainer. The compounds can then be stored in the collection containerswith the software having created an archive consisting of the entirehistory of the compound found in any given well of the collectioncontainer.

Main Unit 100:

Referring to FIG. 2, centrifuge frame 200 supports the centrifuge 110and other components of main unit 100. Centrifuge frame 200 may beformed from steel, iron, aluminum or other metal having sufficientstrength and stiffness to support the weight of the centrifuge 110 andrelated equipment. The metal of which frame 200 is formed is preferablycoated, painted or otherwise treated to resist corrosion from exposureto harsh chemicals used in the operation of the system. Frame 200 may befitted with wheels and manual leveling plates to facilitate positioningand movement of the cleavage/evaporation system.

Centrifuge 110:

As shown in FIG. 1, centrifuge 110 comprises chamber 112, stainlesssteel rotor 114, a software-controlled locking access door 116, drivemotor 118, and a drive motor controller 119. Centrifuge chamber 112 isconfigured as a circular or short cylindrical container comprising a topportion 420 and a bowl portion 422, as shown in FIG. 4. Chamber topportion 420 and bowl portion 422 are preferably made of cast aluminum,which may be anodized, or other material that is resistant to corrosionby cleavage solvents used in the system. The interior surface 426 ofchamber top 420 is formed with a generally concave cross-section toreduce the overall chamber volume. In addition, a plurality of ribs 302are formed in chamber top 420, as shown by dashed lines in FIG. 3. Ribs302 increase the strength of top 420 while providing recessed areas 304for installation of certain hardware, such as shown in FIG. 4. When thesystem is fully assembled, a venting cover 208 is mounted on the top420, covering recessed areas 304 cover. The venting cover 208 fitsclosely around the access openings. Venting cover 208 has a plurality ofports formed therethrough. One or more ports 210 provide means forconnecting a vent line for drawing vapor from vapor cover 208 to thefacility's venting system which may include a blower system and ventlines extending to different areas of the cleavage/evaporation system.One or more second ports may be used to allow a central location forelectrical wiring to be fed into other locations. The venting cover ispreferably made of polypropylene.

The bottom 424 of bowl portion 422 is formed with somewhat convexprofile, with the center sloping upward, to increase strength anddecrease chamber volume. Bowl portion 422 has a flange 428 formed aroundits upper edge with an O-ring seat for retaining an O-ring (not shown)formed therein. The chamber is assembled by aligning lip 430 of top 420with flange 428 then clamping the lip and flange together using a clampring 432 which is tightened by one or more turnbuckles 434 to provide avacuum-tight seal. Clamp ring 432 is preferably made of anodizedaluminum although, generally, fastening hardware used for assembly ofthe centrifuge chamber and rotor and components attached thereto shouldpreferably be formed of 316 stainless steel for optimalcorrosion-resistance.

Chamber top 420 has a front opening 436 and a rear opening 438. Eachopening 436, 438 has a raised lip or flange 440, 442 extending aroundits perimeter which has a flat upper surface with a channel formedtherein for retaining a seal ring 444, 446. In order to provide maximumresistance to the corrosive cleavage solvents, seal rings 444, 446 arepreferably configured with a TEFLON™ exterior and a flexible,compressible silicone core. In one embodiment, each of seal rings 444,446 is formed by inserting silicone tubing into TEFLON™ tubing andfilling the silicone core with air. In another embodiment, the seal ringis formed by coating a silicone O-ring with TEFLON™.

Referring to FIG. 2, the chamber interior is accessible via rear accessdoor 212 and hinged lid assembly 116, both of which are located on thetop surface of chamber top 420. Rear access door 212 is secured overrear opening 438 to chamber top 420 by fastening bolts to provide anairtight seal. Hinged lid assembly 116 comprises a lid body 214 andlatching bar 216. Lid body 214 is shaped to generally fit the outline offront opening 436. Latching bar 216, which is generally rectangular inshape, attaches on its underside to the top surface of lid body 214 andis mounted to chamber top 420 via hinge 218 so that latching bar 216 andlid body 216 can be lifted vertically. As illustrated in FIG. 4, one ormore pneumatic struts 450 are pivotally attached at a first end to tabsextending downward from the distal end of latching bar 216 and at asecond end to chamber top 240 (within space 304). In the preferredembodiment, a pair of struts 450 is used to absorb some of the weight ofthe hinged lid assembly 116 to facilitate raising and lowering of theassembly.

The proximal end 220 of latching bar 216 extends radially beyond theoutermost extent of centrifuge chamber 202 where it provides a handlefor the user to lift the lid assembly 116 and also acts in cooperationwith latching mechanism 222. Extending downward from the proximal end220 of latching bar 216 is a pivotally-mounted fastening latch 224 withlid latch pin 226. Lid latch pin 226 is engaged by hook shank 228 whenthe hook is extended upward by motor-driven telescoping latchingmechanism 230 mounted on top of housing 232 in frame 200. Latchingmechanism holds the chamber lid closed during operation of thecleavage/evaporation system.

In the preferred embodiment, control unit 102 includes software forrelease and locking of lid assembly 116, which is controlled by fiveinputs and two outputs within the DeviceNet™ control network. Thelatching mechanism is engaged by the operator lowering the assembly 116and engaging lid latch pin 226 in hook shank 228. The control unit willdetect contact by an input from the “lid-latch-pin-at-shank” sensor. Inresponse, the control unit triggers two output signals: the“lid-latch-motor-engage-direction” output and the “lid-latch-motor-run”output, which cause linear actuator motor 234 attached to latchingmechanism 230 to retract the shaft of hook shank 228, pulling the hookdown over lid latch pin 226. When lid latch pin 226 enters the hook arm,the “lid-latch-pin-in-arm” sensor is triggered. As the linear actuatorcontinues to pull the shaft of the hook arm 228, lid body 214 is forcedagainst flange 440 to compress seal ring 444 and increase tension in thelatching mechanism 230.

Once the tension reaches a specified level, the linear actuator's motorcurrent will increase to the point where the current sensor generates asignal to inform the control unit that lid assembly 116 is fullyengaged. The control unit stops linear actuator motor 234 by clearingthe “lid-latch-motor-run” output.

Control unit 102 also provides automated release of lid assembly whenthe cleavage/evaporation process is completed by clearing the“lid-latch-motor-engage-direction” output and triggering the“lid-latch-motor-run” output. This output engages linear actuator motor234 to extend the shaft of the hook arm 228. When the shaft of the hookarm reaches sufficient extension, the “lid-latch-pin-at-shank” sensor istriggered. The “lid-latch-released” sensor will then be triggered andthe control unit will stop the linear actuator motor 234 by clearing the“lid-latch-motor-run” output.

The “lid-latch-over-engaged” sensor generates a signal which can be usedto notify an operator that the linear actuator has retracted beyond thepoint where lid body 214 should have contacted flange 444. This sensorcan also be used to notify the operator that the lid latch pin 226 hasnot properly engaged either the hook shank or the hook arm 228.

Referring to FIG. 11, bowl portion 202 of centrifuge chamber 112 has aplurality of ports 1108 formed in the bottom 1106. Each port 1108 isadapted to receive an infrared-transmissive window 132 which ispreferably made of a clear, tempered heat-resistant glass. Each window132 is secured to bottom 1106 by a mounting frame that fits over thewindow and is attached by fastening bolts. A TEFLON® gasket (not shown)is placed between the window and the mounting surface on bottom 1106 toensure a vacuum-tight and corrosion-resistant seal.

A vacuum-access port, indicated by reference numeral 143 in FIG. 1, isformed in the bottom 1106 to provide means for connection of vacuumtubing 145. A vent port 147 can also be formed in the bottom 1106 forattachment to tubing for venting the chamber. A circular opening isformed at the radial center of the chamber to permit centrifuge driveshaft 115 to pass into the interior of the chamber.

A plurality of ports formed in the sidewalls of the chamber bowl portion202 provide access for the dispensing stations 122 and the bar codereader 150. An imbalance sensor (not shown) can be mounted on thecentrifuge body and connected to control unit 102 to shut down the mainunit 100 in the event the system becomes imbalanced. PC 104 can displayan error message indicating the nature of the error.

As illustrated in FIG. 5, rotor 114 is connect to the top of drive shaft115 which is disposed concentrically with the centrifuge chamber 112.Rotor 114 comprises a circular plate of rigid corrosion-resistant metal,such as 316 stainless steel, with a plurality of openings formedtherein, as shown in FIG. 6. A first set of openings 602, each of whichare triangular in shape, extend radially inward from a first radius andare distributed radially evenly around rotor 114. These openings areprovided to reduce the overall weight of the rotor. The second set ofopenings 604, which have a rectangular shape, is formed at a secondradius outside of the first set of openings. Each of the second set ofopenings 604 corresponds to a location at which a compoundcontainer/collection container assembly 404/406 can be positioned forprocessing through the cleavage/evaporation system. In the preferredembodiment, there are twenty-four rectangular openings 604 formed in therotor. Attached to the top surface of rotor 114 at each opening 604 is asupport frame 402 which is adapted to retain the container assembly404/406 during processing.

As shown in more detail in FIG. 7, each support frame 402 has a lowerframe portion 706 and a vertical frame portion 708 formed from acorrosion-resistant material such as aluminum or 316 stainless steel.

Alternatively, support frame 402 can be a molded or machined plastic orpolymer which is corrosion-resistant and sufficiently rigid to preventdeformation of the frame under high speed and/or elevated temperatures.

Lower frame portion 706 is disposed at a fixed angle in the range of 15°to 25°, typically on the order of 15°, which causes a larger surface ofthe fluid in the wells to be exposed for faster evaporation and alsoreduces the risk of bumping. In an alternative embodiment, the frame canbe configured as a swinging bucket which increases its angle by swingingoutward at increased rotor speeds. Both frame portions are open tominimize weight and, in the case of lower frame portion 706, to providean unobstructed path between the heat lamps 138 positioned outside ofwindows 132 and the bottom of heat plate 704 which is seated in theframe 402 with the container assembly 404/406 on top. Support frames 402are attached to rotor 114 by mounting tabs (not shown) which extend fromthe frame for insertion into slots in the rotor and a fastening bolt(not shown) which screws into a threaded bore in rotor 114.

Heat plates 704 are rectangular plates formed from acorrosion-resistant, highly thermally conductive material such asaluminum. A plurality of recesses 710 or shallow wells are formed in thetop surface in an array corresponding to the array of wells incollection container 406, so that the bottom of the wells are receivedwithin the recesses 710 to enhance distribution of heat around theliquid containing the compound for faster evaporation or the solvent.(For ease of illustration, recesses 710 are shown across only a portionof the upper surface of heat plate 704.)

A bearing ring 452 is located in the interior of the centrifuge chamber112 and mounts on the drive shaft 115 and over the drive shaft sleeve454 as shown in FIGS. 4 and 6. The bearing ring 452 is configured as acylinder with an interior recess. Referring to FIG. 5, the bearing ring452 has a circulating system 502 which prevents leakage of corrosivesubstances into the bearings 504. The bearing ring 452 comprises aninternal chamber 506 and a plurality of seals 508 and 510. The internalchamber 506 has two openings, a first opening 512 and a second opening514. The plurality of seals comprises a top seal 508 and a bottom seal510. The top seal 508 is positioned above the first 512 and second 514openings while the bottom seal 510 is positioned directly below eachopening.

Referring to FIGS. 4 and 5, the drive shaft sleeve 454 is configured asa hollowed cylinder with an outside ring 458 having a plurality ofopenings for fastening bolts. The drive shaft sleeve 454 will preferablybe made of type 316 stainless steel. The drive shaft sleeve 454 mountson the bottom of the centrifuge chamber 112 and extends through thecenter opening 456 of the centrifuge chamber 112. The drive shaft sleeveoutside ring 458 bolts into the bottom of the centrifuge chamber 112allowing the drive shaft sleeve 454 to be secured. The drive shaftsleeve 454 has a plurality of sleeve openings 516 and 518 in theinterior edges for allowing circulation to the bearing ring circulatingsystem 502. The sleeve openings 516 and 518 extend from the bottom tothe top. A plurality of bearings 504 mount inside the drive shaft sleeve454. The sleeve openings comprise of a first sleeve opening 516 and asecond sleeve opening 518. The first sleeve opening 516 is connected toa gas source 129. The gas source 129 pumps nitrogen up the first sleeveopening 516 and into the first opening 512 of the bearing ring 452. Thenitrogen is forced through the internal chamber 506 of the bearing ring452 because the top 508 and bottom 510 seals allow for the internalchamber to be sealed. The nitrogen is funneled out of the internalchamber 506 to the second opening 514 of the bearing ring 452 and downthrough the second sleeve opening 518 out to a vent line connected tothe ventilation system 170.

Referring to FIG. 1, the drive shaft 115 is configured as a long,cylindrical tube. The drive shaft 115 will preferably be made of a type316 stainless steel. The drive shaft 115 has a first end 164 and asecond end 166. The first end 164 is positioned in the interior of thecentrifuge chamber 112 and extends through the drive shaft sleeve 454,through a drive shaft encoder 168, and to the second end 166 which isattached to the center of a drive belt gear 172. The drive belt gear 172is a flat, circular plate with notches around the outside edges to allowa drive belt 174 to notch into place. The drive belt 174 is attached toa drive motor 118 which is mounted to the centrifuge frame 200.

The drive motor 118 is a servomotor with the ability to operate atdifferent rotational speeds. As the drive motor 118 rotates, the drivebelt 174 is engaged causing the drive belt gear 172 to turn. The drivebelt gear 172 drives the drive shaft 115 which in turn spins the rotor114. Selection and incorporation of such a drive motor will be apparentto those of skill in the art.

Referring to FIG. 1, a drive motor controller 119 connects to the drivemotor 118 using an interface cable. The drive motor controller 119connects to a control adapter that connects to the control unit 112. Thecontrol unit 112 sends positioning commands to the control adapter thatare communicated to the drive motor controller 119. The drive motorcontroller 119 can send positioning data to the control unit 112 andmake positioning adjustments as required by the control unit 112.

The drive shaft encoder 168 is used to track the position of the rotor114. The drive shaft encoder 168 mounts on the drive shaft 115 withfastening screws. The drive shaft encoder 168 has a graduated disk witha periodic grating of lines and gaps. A second track carries a referencemark. The reference mark defines an absolute reference position on thecircular graduation and is permanently assigned to exactly one measuringcount. The position value is determined by counting the measuring steps.The drive shaft encoder 168 is connected to the drive motor controller119. The output signal of the drive shaft encoder 168 is sent to thedrive motor controller 119 for determining the rotor 114 positioning.Selection and incorporation of such a drive shaft encoder will beapparent to those of skill in the art.

Container Assembly 404/406:

Sample container 404 and collection container 406, which make upcontainer assembly 404/406, are of a molded, plastic construction. Theplastic material used will preferably have a high tensile strength andbe heat and chemical resistant.

As illustrated in FIG. 17, compound container 404 has a generallyrectangular body 1702 on top of base extensions 1704, 1706 which act asfeet when the container is placed on a flat surface. Rectangular body1702 has a plurality of wells 1710 extending downward from the topsurface 1708. In the preferred embodiment, compound container 404 has 96wells arranged in an array corresponding to the conventional 96-wellformat (8 wells×12 wells). The shape of wells 1710 will depend on theconfiguration of the solid support, and is selected so that the solidsupport will fall fully down to the bottom of the well in which itplaced. In the exemplary embodiment, the solid support comprises apartially porous disk-shaped container with resin inside, which iscommercially-available from IRORI (San Diego, Calif.) as the NanoKan™.An example of this type of solid support 2102 is shown in the left-mostwell 1710 of FIG. 21. For this configuration, the compound container'swells 1710 have a rectangular cross-section, as shown in FIGS. 17 and20, and a U-shaped width with well bottom 2104 slightly larger than thediameter of the solid support 2102, as illustrated in FIG. 21. Inanother example, where the solid support is one or more spherical beadswithout a container, the well may have a circular cross-sectional shapedimensioned to receive the spherical bead. A number of other forms ofsolid supports are known, including tubes, pins, crown, disks, balls,cubes or blocks, and porous containers for retaining particulatematerial (see, e.g., U.S. Pat. No. 5,961,923.) the wells of samplecontainer 404 can be sized as needed to accept virtually any type ofsolid support for purposes of the invention.

Further detail of the exemplary embodiment is illustrated in FIGS. 25and 26, showing the side view of a well 1710 with solid support 2102 incleaving solution 2502. Bridge portion 2504 slopes upwardly, away fromthe bottom and may be, as shown, narrower than well 1710, andparticularly solid support 2102, so that only solution containing thecleaved compound can pass across bridge portion 2504 and down into draintube 1712 when the centrifuge is activated as described below. Solidsupport 2102 is retained in well 1710 due to primarily to thecentrifugal force. Therefore, it is not necessary for bridge portion2504 and drain tube 1712 to be smaller in diameter that the bead orother solid support. It may be desirable to ensure that a small solidsupport does not accidently become lodged in the drain tube 1712 byplacing a frit or filter at the entrance to the drain, near the bridgeportion. Drain tube 1712 is essentially a bore extending from the top ofcompound container 404 through the bottom and downward therefrom to formnozzle 1714, thus providing a fluid transfer pathway from the samplecontainer 1710 out to the corresponding well in the collectioncontainer.

Referring again to FIG. 17, base extensions 1706 extend laterally awayfrom body 1702 with a band 1716 extending between base extensions 1706.The lateral extension acts to increase the overall length of compoundcontainer 404 so that it fits over the collection container 406, whichhas the dimensions of a conventional 96-well plate. A bar code 1720 isaffixed to or imprinted on band 1716 to permit tracking of the compoundsin the compound container. One of the base extensions 1706 has adiagonal portion 1722 formed at its corner to provide an orientationindicator which restricts the orientation of compound container 404 inthe centrifuge to one where the bar code 1720 is readily visible throughthe bar code reader window 152.

As illustrated in FIGS. 23 and 24, collection container 406 has arectangular body with a plurality of cylindrical wells 2302 with roundedbottoms 2402 arranged in an array corresponding to the array of wells1710 in compound container 404. In the preferred embodiment, collectioncontainer 406 is a 96 well plate with an 8×12 array. Positioning andspacing of the wells 2302 closely matches that of nozzles 1714 whichextend from the bottom of sample container 404. Wells 2302 extenddownward from top surface 2312 into the spacing between sidewalls 2304,2306, 2308 and 2310. The bottom 2402 of each well is slightly recessedfrom the bottom edge 2404 of collection container 406. As previouslydiscussed, heat plate 704 has a plurality of recesses 710 formed thereinwhich correspond to the rounded well bottoms 2402, thus providing formore uniform distribution of heat around the outer surface of the wellbottoms 2402. In order to provide contact for heat distribution, theseparation of sidewalls 2304, 2306, 2308 and 2310, i.e., the insidedimension of collection container 406, must be slightly more that thedimensions of heat plate 704, so that heat plate 704 fits within thecontainer's sidewalls to permit contact with the bottom of collectioncontainer 406. The external dimensions of collection container 406 mustbe slightly smaller that the interior dimensions between base extensions1704 and 1706, so that the base extensions fit over the corners ofcollection container 406 to form container assembly 404/406. As bestshown in FIG. 22, bar code 2202 is affixed or imprinted on sidewall 2304at a position below the compound container bar code 1720, so that bothbar codes are clearly visible for reading by bar code reader 150. Anorientation aligner 2314 comprising a diagonal across one corner of thecontainer ensures that the two containers can be assembled only whenthey are correctly oriented, which, in turn, ensures that the bar codes1720 and 2202 are clearly visible for reading.

Sample container 404 is joined to the top of collection container 406 bysliding the base corners 1704 and 1706 over the corners on top of thecollection container. The array of nozzles 1714 extending from compoundcontainer 404 closely match the array of wells 2302 in collectioncontainer 406.

In an alternative embodiment, the sample and collection containerassembly is integrated into one structure, as illustrated in FIG. 30, toform a transferless container assembly 3002. The general configurationof container assembly 3002 is similar to that of collection container406 in that the wells 3004 are formed as a plurality of closed vesselsformed in an array, such as a 96-well plate. The bottoms of wells 3004are preferably rounded to fit within the recesses in the heat-diffuserplates 710. Container assembly 3002 differs from collection container406 in that the inner diameter of each well 3004 is reduced at a pointpart way down the inner volume so that the solid supports 3008 areprevented from falling all the way to the bottom of well 3004. Thediameter restriction can be a reduced diameter over-all, as shown, orcan be one or more protrusions, such as ribs, ridges, rings or tabs,extending toward the axial center of the well which create a spacesmaller than the diameter of solid support 3008 to prevent it from goingany deeper into the well. The space below the diameter restrictiondefines a collection space 3010 into which the cleaved sample can becollected after it is cleaved from the bead 3008. After the evaporationstep is performed to remove the solvent, the dried cleaved sample 3012remains in the bottom of collection space 3010, and container assembly3002 can be tipped over to remove the solid supports. The dried cleavedsample, which generally has a sticky, viscous consistency, will remainin well 3004 until it is resolubilized or removed using some otherappropriate method.

In a second alternate embodiment, the sample/collection containerassembly is adapted for use in solid phase DNA purification. Asillustrated in FIG. 31, sample/collection container assembly 3102comprises sample container 3104, waste or collection container 3106.

Sample container 3104 has an array of wells 3110, each of which isessentially a column such as used in column chromatography, i.e., acylindrical well 3112 which reduces at its lower end to a funnel-likestructure 3114 that continues as a narrowed drain tube 3108 extendingfrom the bottom of container 3104. Porous plugs 3116, 3118, formed ofporous glass or other appropriate material, are disposed at the top andbottom of the well 3112, respectively, on either side of the solidsupport 3120, to permit solvent to be introduced at the top and topermit fractionated molecules to pass through and out of samplecontainer 3104 at the bottom.

A second container, waste or collection container 3106 interfits withsample container 3104 and has an array of wells 3122 arranged in apatterns corresponding to wells 3110 and drain tubes 3108 of samplecontainer 3104, so that when the two containers are fitted together,drain tubes 3108 extend into the corresponding well 3122. The washingsolutions or eluting agents are introduced using the solvent dispensingsystem as described. For purification steps, where impurities areremoved, the solution carries the impurities through solid supports 3120and porous plugs 3118 into wells 3122 as a waste solution. In oneembodiment of the method, the operator opens the centrifuge chamberafter completion of the purification step, removes the container 3106containing the waste material and replaces it with a clean container3106 which can be used for cleavage of the DNA from the solid support.In another embodiment, a third container can be used for receiving thewaste solution from drains 3108 and directing the solution, usingcentrifugal force, to a waste reservoir in the centrifuge chamber viagenerally horizontal channels formed in the container body. Such channelwould exit the container body in a direction coincident with thedirection of centrifugal force, so that spinning of the container bodycauses the solution to exit the container. See, for example, the circles3130 indicated by dashed lines in FIG. 31, which indicate ports whichcan be connected to a drain manifold leading to a waste collectionreservoir within or outside of the centrifuge chamber. In yet anotherembodiment, the wells of the waste collection container could beconfigured in a manner similar to sample container 404, with a bridgestructure that prevents the solid support and attached DNA from escapingthe main well, while the waste solution following a purification steppasses over the bridge and out channels connected to a waste collectionreservoir.

Gas Supply Subsystem:

As illustrated in FIG. 1, the gas supply system comprises a nitrogensource 129, a plurality of regulators 182, 183, a pressure sensor 184,and tubing 186. The gas supply system is connected to both dispensersubsystem 120 and to centrifuge chamber 112, providing a purge gas toboth subsystems. In the dispenser subsystem 120, nitrogen is used todisplace liquid during dispensing. In the centrifuge chamber 112,nitrogen is introduced into the chamber after it is evacuated to providean inert atmosphere within which the cleavage and evaporation operationsare performed. Nitrogen source 129 is a small high pressure cylinder inthe preferred embodiment, however other inert gases may be used.Regulator 182, which is manually adjustable, regulates nitrogen sourcepressure. Regulator 183, also manually adjustable, regulates pressureinto the dispenser subsystem 120. Dispense pressure regulator 183connects via tubing 186 to in-line dispenser displacement valve 185 theninto dispenser head 418, and into dispenser bypass valve 187 for routingto centrifuge chamber 112. Each valve 185, 187 is pneumaticallycontrolled by a control adapter in response to a signal generated bycontrol unit 102.

Solvent Supply Subsystem 120:

All components of solvent supply subsystem 120 that come in contact withthe solvents are made from acid-resistant materials, thus permitting thehandling of solvents used in the cleavage of chemical compounds in asealed chamber, avoiding exposure of personnel to hazardous chemicalsand risk of damage to equipment from corrosion. Referring to FIG. 13, inthe preferred embodiment, solvent supply subsystem 120 comprises twodispensing stations 122, 122′, two source containers 124, 124′ and acirculation system for simultaneously filling all wells of a compoundcontainer 404 with cleaving solutions.

Dispensing stations 122, 122′ each comprise an internal portion,consisting of dispensing head 410 and an external portion 1302 which isattached at the exterior sidewall of the chamber bowl portion 202 atports 1304. Details of each dispensing station 122 are shown in FIGS.14-16. Dispensing station 122 comprises a housing 1406, a dispenser head410, dispensing arm 1902 (shown only in FIGS. 18 and 19) for raising andlowering dispenser head 410, and a reservoir chamber 1408. Housing 1406is comprises a top portion 1410 and a bottom portion 1412 which definean interior recess 1502. Top and bottom portions 1410 and 1412 are madeof stainless steel and are secured together with fastening bolts. AnO-ring or other seal is included when assembling the top and housing toensure a vacuum-tight seal. Housing 1406 has a flange portion 1402 witha plurality of fastening bores and an O-ring seat 1404 formed therein. ATEFLON® O-ring is fitted into seat 1404 for providing acorrosion-resistant, vacuum-tight seal between the chamber sidewall andthe dispensing station once the mounting bolts (not shown) aretightened. An opening is formed in top portion 1410 which is covered bya removable cover 1414. When cover 1414 is removed, the opening providesaccess to an adjustment screw the permits a small side-to-sideadjustment of the dispenser head 410. Bottom portion 1412 has one ormore openings 1424 through its sidewall through which bundles of tubing414 can pass between the dispensing head 410 and reservoir chamber 1408.

Dispenser head 410 extends from housing 1406 through port 1304 intocentrifuge chamber 112 to engage sample containers 404 to confirm properseating and to fill sample containers 404 with cleaving solution. Theproximal end of dispenser head 410 is pivotably mounted within housing1406 so that it can be raised and lowered. Dispenser head 410 ispreferably made of polyvinylidene fluoride (PVDF) and has a top cover1416 and a bottom portion 1418 which define a hollow body through whicha plurality of tubes 414 (shown in FIG. 15) can be fed through openings1424 to provide fluid transfer from reservoir chamber 1408 to aplurality of dispensing tips 412 extending downward near the distal end1420 of dispensing head 410. The dispensing tips 412 will preferably beformed from stainless steel tubing to provide sufficient rigidity toprovide more accurate positioning. The distal end of each tube 414 isconnected to the upper end of each dispensing tip 412 inside ofdispenser head 410 and the tips 412 pass through bores 1504 formedthrough the lower wall of bottom portion 1418. The proximal end of eachtube 414 is disposed at or just above the fluid surface level of itscorresponding reservoir well 1432. Alternatively, the proximal end ofeach tube 414 can extend to the bottom of the reservoir well 1432 aslong as compensation is made for the well volume that will be taken upby the tubing. It should be noted that for ease of illustration, due tothe large number of tubes actually used in the exemplary embodiment,only a small number of tubes 414 is shown in FIG. 15, and the proximalends or tubes 414 are not shown terminating at a position relative toreservoir wells 1432. It will be readily apparent to one of skill in theart that one reservoir well 1432 corresponds to one tube 414 whichcorresponds to one bore 1504 and one dispensing tip 412.

Bottom portion 1418 has a plurality of tabs 1422 extending outward anddownward from the sides. Tabs 1422 are spaced apart at a distance thatclosely fits over the top of sample container 404 and are used to securecontainers sets 404/406 when dispenser head 410 is lowered. As shown inFIG. 19, dispenser head 410 can be raised and lowered by dispenser armassembly 1902 which is connected to the underside of the dispenser head.Opening 1904 is formed in housing bottom 1412 permitting dispenserplunger 1908 of dispenser arm assembly 1902 to enter the housing 1410.Dispenser sleeve 1906 is attached to the bottom of bottom portion 1412to guide dispenser plunger 1908 through opening 1904 and to provide avacuum seal between dispenser arm assembly 1902 and the housing 1406.Dispenser plunger 1906 attaches at its upper end to the bottom ofdispenser head 410 via hinge 1910. The lower end of plunger 1906pivotably attaches to rocker plate 1912 which, in turn, pivotablyattaches to dispenser head actuator 1802 at pivot point 1914. Rockerplate 1912 pivots relative to center pivot 1916.

To lower dispenser head 410, dispenser head actuator 1802 is activatedpneumatically to overcome a downward bias provided by a bias spring (notshown) in actuator 1802, lifting the actuator side of rocker plate 1912and lowering the plunger side. When actuator 1802 is inactive, dispenserhead 410 is in the raised position, allowing container assemblies404/406 to move freely with rotation of rotor 114. Air pressure foractivation of actuator 1802 is controlled by opening an actuator valvein response to commands of control unit 102. Dispenser head 410 includesa plurality of sensors for detecting improper mounting of container sets404/406 or missing container sets on support frames 402. If a containerset is discovered to be missing or improperly mounted, the control unitwill notify the operator to correct the problem.

Referring to FIG. 14, reservoir chamber 1408 is mounted on the side ofthe housing 1406. As with the other components of the dispensing station122, reservoir chamber 1408 must be vacuum-tight. Reservoir chamber 1408is made of polyvinylidene fluoride (PVDF) to be able to withstand thecorrosive solvents used in the system. The top 1426 is glass to permitvisual confirmation of the filling operation. Stainless steel frame 1428is bolted over top 1426 to seal chamber 1408. Fill container 1430 islocated inside reservoir chamber 1408 to hold liquid solution andtransfer it into tubes 414 for feeding to dispenser head 410. Asillustrated in FIGS. 27 and 28, fill container 1430 is a generallyrectangular block of TEFLON® with a plurality of solvent reservoir wells1432 formed therein, corresponding in number to the number of tubes 414and the number of wells 1710 and 2302 in compound container 404 andcollection container 406, respectively. (It should be noted that forease of illustration, only a small number of tubes 414 are shown in FIG.15 while, in fact, there would be one tube 110 corresponding to eachreservoir 1432.) Each reservoir well 1432 is surrounded by a pluralityof much smaller diameter bores 2702 which extend through the fullthickness of the body of fill container 1430, exiting at the bottom 2802in the pattern shown in FIG. 29. Bores 2702 act as drains to removeexcess solvent when reservoir chamber 1408 is filled with liquid, to alevel above the top of fill container 1430, then drained, causing theliquid to level off precisely at the tops of each reservoir well 1432,even with top surface 2704 of fill container 1430. Excess solvent isreturned to source containers) 124, leaving a measured amount of solventin each reservoir well 1432. As previously described with respect toFIG. 1, gas supply 129 supplies nitrogen to reservoir chamber 1408 viatubing 186 and dispenser displacement valve 185. The nitrogen increasesthe pressure within reservoir chamber 1408 creating a pressuredifferential which causes liquid to be forced through tubing once thereservoir wells 1432 have been filled with the desired amount ofsolvent.

The liquid solutions handled in solvent supply subsystem 120 can becorrosive or non-corrosive solutions, for example, trifluoroacetic acid(TFA), dichloromethane (DCM) or dichloroethane (DCE), or a combinationthereof, for use in cleavage of synthesized chemical compounds. Forbiological applications, such as DNA purification, the solvent can be adetergent, typically non-ionic, buffering solution, deionized water, orany eluting reagent appropriate for use in DNA purification as are knownin the art. In the exemplary embodiment illustrated in FIG. 13, eithersolvent source 124 and 124′ can be selected to supply one or bothdispensing stations 122 and 122′. As shown, dispensing station 122 isconnected through first dispenser supply valve 1306 and tubing 1310 toboth first source pump 126 and second source pump 126′ via aT-connection within tubing 1310. Similarly, dispensing station 122′ isconnected through second dispenser supply valve 1306′ and tubing 1312 toboth first and second source pumps 126 and 126′ via a T-connection intubing 1312. Tubing 1314 provides connection between the two dispensingstations 122 and 122′ and to the dispenser waste pump 1308 that feedsinto waste collection system 160, and specifically into waste reservoir162. Both source pumps 126 and 126′ are reversible, providing flow inboth directions. A source spill sensors can be included in cabinetscontainer the source containers for detecting spillage.

Sensors can be included to monitor the filling of each reservoir chamber1408. In the preferred embodiment, a dispenser overfill sensor 1314 anda dispenser fluid sensor 1316 are used to monitor liquid solution levelsin the reservoir chamber. The two sensors attach to a TEFLON® tube (notshown) that connects into reservoir chamber 1408.

During operation, control unit 102 directs centrifuge rotor 114 toincrement, placing a container set 404/406 in front of a dispensingstation 122. Dispenser head 410 is lowered to confirm that container set404/406 is properly mounted on support frame 402. If mounting isincorrect, control unit 102 will notify the operator to fix the problem.If correct mounting is confirmed, the dispensing process can begin.

Referring to FIGS. 1 and 13, the solvent supply subsystem 120 system isactivated by control unit 102. The system is usually primed beforedispensing begins by running a dispensing cycle with no actualdispensing. Dispenser supply valve 1306 for the first dispensing station122 is opened while dispenser supply valve 1306′ for the seconddispensing station 122′ is closed. The source pump for the desiredsolvent (either 126 or 126′) is started and liquid solution from theselected source container 124 or 124′ is pumped into reservoir chamber1408 of the first dispensing station 122. Reservoir chamber 1408 is thenfilled after which control unit 102 will direct the source pump 126 or126′ to reverse flow, causing the excess liquid solution to drain fromreservoir chamber 1408 back into the appropriate source container, thusconserving solvent. Alternatively, after reservoir chamber 1408 isfilled, the source pump 126 or 126′ is turned off and dispenser wastepump 1308 is turned on so the liquid solution can drain into the wastebasin. The waste pump 1308 is only used for the priming process and isnot used during actual dispensing. Once completed, the dispenser wastepump 1308 or the source pump 126 or 126′ is shut off.

After the priming process has been completed, the same procedure willoccur except that once reservoir chamber 1408 has been drained, thereservoirs 1432 in fill container 1430 will be filled with liquidsolution. Bores 2702 which surround reservoirs 1432 remove excesssolvent when reservoir chamber 1408 is filled with liquid, causing theliquid to level off precisely at the tops of each reservoir well 1432,so that each contains a measured amount of solvent. Excess solvent isreturned to source container 124 or 124′. Nitrogen is introduced intochamber 1408 to force the liquid through tubing 414, out thecorresponding dispensing tip and into the wells 1710 of compoundcontainer 404. This procedure is repeated until all the container sets404/406 on rotor 114 are filled and the rotor is activated to spin atthe appropriate speeds for cleavage and evaporation.

In an exemplary embodiment, the reservoir wells 1432 in each dispensingstation 122 or 122′ have a different volume, and the same solvent can bedispensed by each station, with a larger volume being dispensedinitially by one station 122, and a smaller volume being dispensed bythe other station 122′ at a later point during the process, to top offwells 1710 during cleavage to compensate for evaporation or other lossesof solvent. For example, for cleavage of a chemical compound from asolid support, station 122 would dispense 250 microliters of a 50:50TCA/DCM mixture at the beginning of the cleavage process, then afterincubation for about one hour, station 122′ would dispense 100microliters of the same mixture, after which incubation would resume.After completion of incubation, the samples could be rinsed withmethanol by switching to a different source container containingmethanol and dispensing methanol via one of dispensing stations 122 or122′.

Temperature Control Subsystem 130:

The temperature control subsystem 130, shown in FIG. 1, provides theability to independently control and monitor the temperature of thecentrifuge 110. In particular, temperature control subsystem 130addresses the problems that occur when attempting to evaporate a solventwhile pulling a vacuum. According to well-known principles ofthermodynamics, i.e., PV=RT, under vacuum the temperature drops,resulting in a very slow rate of evaporation of the solvents. Inaddition, wells in the center of the container arrays will evaporatemore slowly because they tend to be cooled by the surrounding wells.Thus, heat input is required to maintain a constant temperature.

Referring to FIGS. 4, 11, and 12, temperature control subsystem 130comprises a heat/temperature controller 1104/1206, a plurality of heatlamps 138, a plurality of heat plates 704, at least one thermal sensor1102, a plurality of resistive heaters 1202, and a plurality oftemperature sensors 1204. The temperature control subsystem 130 has twomain functions: the first is to regulate the temperature of the heatplates 704 to maintain a constant temperature and the second is toregulate the temperature of centrifuge chamber 112.

The heat/temperature controller 1104/1206 comprises a housing whichhouses a control element, and an interface to the control unit 112.

The temperature/heat controller housing is configured as a box which canbe attached to the exterior bottom of the centrifuge chamber or mountedwithin the support frame of the centrifuge assembly. The control elementcomprises a circuit board with one or more integrated chips (ICs)mounted thereon. A heat/temperature control program, which is stored inone of the control element's ICs, allows the heat/temperature controller1104/1206 to independently control and manage all components of thetemperature control subsystem 130.

Heat/temperature controller 1104/1206 includes an interface forcommunicating with control unit 102 to continuously reporttemperature-related information and receive updated temperaturedirectives from the control unit 102. Temperature control subsystem 130functions by independently controlling and adapting heating operationsto maintain a constant temperature during evaporation as determined bycontrol unit 102. Specifically, the control subsystem 130 monitors theamount of heat-input required to maintain the pre-determined temperatureof the samples, which is typically at or slightly above roomtemperature. (Again, it should be noted that since the evaporation isoccurring under a vacuum, the temperature in the chamber is much lowerthan room temperature.) Temperature control is achieved adaptively,preferably by way of a neural network, software for which is maintainedin control unit 102, or other similar adaptive software routine,allowing it to rapidly respond to, and even anticipate, temperaturechanges. Exemplary neural network software is commercially availableunder the trademarks “Thinks™” and “ThinksPro™”, published by LogicalDesigns Consulting of La Jolla, Calif. Selection of other appropriatesoftware is within the level of skill in the art. Temperature controlsubsystem 130, in conjunction with the neural network, monitors the heatinput required to increase the temperature of the heat plates whilemeasuring the temperature ramping at the heat plates 704 to determinehow soon the target temperature will be reached, then graduallydecreases the heat input, thus minimizing temperature overshoot, andapplying only the required amount of heat input. By controlling thetemperature so precisely to ensure uniform evaporation, it is possibleto accurately predict when evaporation will be completed, so that theevaporation step can be automatically shut down. This provides asignificant advantage over current practices of estimating completion ofevaporation by calculating how long it takes to evaporate a given volumeof solvent assuming a constant evaporation rate, then adding a fixedamount of time to compensate for non-uniformity. Such prior artpractices often result in overheating and burning of samples, anddiminishes overall system throughput by taking more time to complete theevaporation process than may actually be necessary.

As illustrated in FIG. 11, an infrared heat lamp 138 is mounted beloweach heat-transmissive window 132 in the bottom 1106 of centrifugechamber 112 with the lamp facing directly towards heat-transmissivewindow 132. Each heat lamp 138 can be independently turned on and off byheat/temperature controller 1104/1206.

Referring to FIG. 7, heat plates 704 are rectangular plates formed froma corrosion-resistant, highly thermally conductive material such asaluminum. A plurality of recesses 710 or shallow wells are formed in thetop surface in an array corresponding to the array of wells incollection container 406 as shown in FIG. 23, so that the bottom of thewells are received within the recesses 710 to enhance distribution ofheat around the liquid containing the compound for faster evaporation orthe solvent. (For ease of illustration, recesses 710 are shown acrossonly a portion of the upper surface of heat plate 704.)

Referring to FIG. 11, a thermal sensor 1102 is located in a recessformed in the bottom of heat plate 704. Such a sensor can be placed in asingle heat plate 704 or a plurality of sensors can be placed in anumber of heat plates distributed around the rotor. The thermal sensor1102 attaches to an electrical wire that connects to an optical (IR)transmitter 135. For protection against corrosion, both thermal sensor1102 and the electrical wire are encased in TEFLON® tubing. The optical(IR) transmitter 135 has a sealed polyvinylidene fluoride (PVDF) housingand is mounted in the center of rotor 114 by clips. The optical (IR)transmitter 135 is battery powered and has a built in mercury switch.The mercury switch controls battery usage by enabling power to theoptical (IR) transmitter 135 only when the rotor 114 is spinning andturns off the power when the rotor 114 is inactive.

An IR-transmissive window 134 is mounted and sealed within top 420 ofcentrifuge chamber 112, directly above the optical (IR) transmitter 135.A detector 136 is positioned outside of the window for receiving thetransmitted signal and converting the infrared signal to an electricalsignal which is communicated to the heat/temperature controller1104/1206.

In one example implementation, the rotor 114 spins container assembly404/406 mounted on heat plates 704 past each heat-transmissive window132. As the container assembly 404/406 pass each window, the bottom ofthe heat plates 704 are exposed to the infrared heat lamps 138. As thetemperature of heat plates 704 rises, thermal sensor 1102 in contactwith one of the heat plates 704 provides a signal indicative of theplate's temperature to the optical (IR) transmitter 135 located belowthe light-transmissive window 134 in the top of centrifuge chamber 112.Optical transmitter 135 converts the signal to an optical signal whichis detected by detector 136 positioned outside of light-transmissivewindow 134. Detector 136 converts the optical signal to an electricalsignal which is communicated to the sample heat controller 1104 toprovide feedback for controlling the heat lamps 138.

Referring to FIG. 12, additional heat to the centrifuge chamber 112 isprovided by resistive heaters 1202 mounted on the top and bottom of thecentrifuge chamber 112. The resistive heaters 1202 will preferably beevenly dispersed to provide uniform heating of the centrifuge chamber112. The top and bottom resistive heaters 1202 can be independentlycontrolled by the chamber temperature controller 1206. For example, thetop resistive heaters 1202 can be engaged while the bottom resistiveheaters 1202 are not engaged. One or more temperature sensors 1204mounted on the outside of the chamber provides feedback to the chambertemperature controller 1206 for controlling the chamber temperature.

A chamber temperature sensor 133, shown in FIG. 1, is included to shutdown all temperature control subsystem 130 components if the temperatureof the centrifuge chamber 112 exceeds a pre-determined level. Thechamber temperature sensor 133 is mounted on the bottom of thecentrifuge chamber 112.

Vacuum Subsystem 140:

All components of vacuum subsystem 140 that come in contact with thesolvents are made from acid-resistant materials, thus permitting theautomated handling of solvents in a sealed chamber, avoiding exposure ofpersonnel to hazardous chemicals and risk of damage to equipment fromcorrosion. As illustrated in FIG. 1, vacuum subsystem 140 maintains avacuum within the centrifuge chamber 112, while monitoring andcontrolling the internal pressure of the centrifuge chamber 112. Vacuumsubsystem 140 comprises a vacuum controller 142, a diaphragm pump 146, aRoots blower-type pump 144, a condenser 148, and a plurality of valves141 and 147.

Vacuum controller 142 controls the operation of the diaphragm pump 146and is connected to a control adapter, which interfaces with controlunit 102. Pressure sensor 194 is connected to vacuum controller 142 topermit monitoring of the pressure in centrifuge chamber 112. Vacuumcontroller 142 reports pressure information to control unit 102 andreceives commands regarding the operation of the pumps, and pressurerelief valve 147.

Diaphragm pump 146 compresses vapors pulled directly from the centrifugechamber 112 or through the Roots blower-type pump 144, depending on theposition of pump selector valve 141. The diaphragm pump 146 is used forinitial pumping down to a first vacuum level, which, in the exemplaryembodiment, is on the order of 50 mbars. In order to protect diaphragmpump 146 against corrosion, all of its components that are exposed tosolvent vapor pulled from centrifuge chamber 112 are preferably formedfrom or coated with TEFLON® or other protective coating.

The condenser 148 is connected downstream from diaphragm pump 146 tocondense solvent vapors pumped from centrifuge chamber 112, thuspreventing the release of vapors into the atmosphere. Condenser 148 iscooled by water from the recirculating chilled water bath 188, andprovides the advantage of not requiring liquid nitrogen such as isrequired in conventional cold traps. Condensed vapors collected on thecoils of condenser 148 are drained into waste reservoir 162, while airentering into the condenser is exhausted via appropriate tubing to thesystem vent 170. Waste reservoir 162 has a double containmentarrangement and includes a waste spill sensor 190 and a waste fullsensor 192 to detect spills from the primary container.

Roots blower-type pump 144 is a mechanical pump used for furtherreducing the pressure in centrifuge chamber 112 once it has been broughtdown to the first vacuum threshold by diaphragm pump 146. In combinationwith diaphragm pump 146, Roots blower-type pump 144 can decrease thepressure inside centrifuge chamber 112 to about 1 mbar. When the pump isin use, the exhaust of Roots blower-type pump 144 is connected todiaphragm pump 146 so that the vapors drawn out of centrifuge chamber112 by pump 144 can be compressed and removed from the exhaust. Rootspump 144 is connected to a control adapter, which interfaces controlunit 102. Control unit 102 directly controls all operational aspects ofthe Roots blower-type pump 144.

The plurality of valves includes a pump selector valve 141 and a chamberpressure relief valve 147. The pump selector valve 141 is connected acontrol adapter which interfaces with control unit 102. The pumpselector valve 141 is an electromechanically-operated ball valve thatconnects by tubing to Roots blower-type pump 144 and diaphragm pump 146.Control unit 102, communicating via the control adapter, can positionthe pump selector valve 141 to select pumping by either Rootsblower-type pump 144 or diaphragm pump 146.

Chamber pressure relief valve 147 is a spring-loaded valve mounted nearthe bottom of the centrifuge chamber 112 for emergency release ofpressure in centrifuge chamber 112 in the event the pressure exceeds apre-determined level.

In an example implementation, the control unit 102 will activate pumpselector valve 141 to select the appropriate pump depending on whichprocess is to be performed. In the first stage of chamber evacuation,pump selector valve 141 is positioned to direct chamber exhaust todiaphragm pump 146 which compresses the vapors and passes them to thecondenser 148 where the vapors are condensed on coils cooled by waterfrom recirculating chilled water bath 188. Any vapors remaining in gasform are exhausted to vapor venting system 170 while the condensedvapors are drained via tubing to waste disposal system 160. Diaphragmpump 146 continues to draw exhaust from chamber 112 until the internalpressure reaches a first vacuum level of about 50 mbar, at which pointRoots blower-type pump 144 is engaged.

In the second stage of chamber evacuation, pump selector valve 141 isrepositioned to channel the chamber exhaust to Roots blower-type pump144. Roots blower-type pump 144 reduces the chamber pressure from about50 mbar to about 1 mbar. The exhaust of Roots blower-type pump 141 isdirected to diaphragm pump 146 and to condenser 148 for removal ofsolvent vapors from the exhaust.

Bar Code Reader 150:

Referring to FIG. 1, the bar code reader 150 is positioned to face thebar code window 152 on the centrifuge chamber 112. The bar code reader150 is mounted to a pneumatically actuated positioner 154 that providesfor he bar code reader 150 to be moved up and down. Air pressure foractivation of actuated positioner 154 is controlled by opening anactuator valve in response to commands of control unit 102.

In an exemplary embodiment, rotor 114 positions container assembly404/406 so that it is in front of bar code window 152 and bar codereader 150 is positioned in the down position. Bar code reader 150 isaligned with collection container bar code 2202 to allow scanning. Afterscanning has taken place, control unit 102 opens an actuator valve sothat the actuated positioner 154 is moved upward to align bar codereader 150 with the compound container bar code 1720. Bar code reader150 scans the compound container bar code 1720 and the rotor is theninitialized by control unit 102 to move to the next container assembly404/406 into position for reading by bar code reader 150. At this point,bar code reader 150 is in the “up” position and will scan the compoundcontainer bar code 1720 of the new container assembly 404/406. Controlunit 102 will then close an actuator valve so the actuated positioner154 will move bar code reader 150 to the “down” position. Bar codereader 150 will repeat the same process until all container assemblies404/406 are scanned. It will be apparent to those of skill in the artthat other positioning schemes may be used to position bar code reader150 when needed for reading two separate bar codes, which may includethe use of optical means such as rotating mirrors, or may utilize twoseparate bar code readers.

System Operation:

In a first exemplary implementation, sample chemical compounds to becleaved from their solid supports are placed in a container assembly404/406 then loaded into the cleavage/evaporation system by opening thehinged lid 116 of the centrifuge 110 and placing the container sets404/406 and heat plates 704 onto support frames 402 located on top ofthe rotor 114. The operator may turn the rotor 114 by hand in order toaccess and load all of the support frames 402 with container sets404/406 and heat plates 704, or a switch or other control means can beused to incrementally turn the rotor to present the loading stations oneat a time.

Once all desired support frames 402 are filled, hinged lid 116 is closedand locked into place. It should be noted that not all frames need to befilled, and the only requirement is that the support frames be filled inan arrangement that is balanced on the rotor. Vacuum subsystem 140 isengaged and starts running the diaphragm pump 146 to remove the ambientair, then the gas supply subsystem backfills centrifuge chamber 112 toatmospheric pressure with nitrogen. The chamber heating system remainson while the system is idle and during cleavage to maintain the chambertemperature at a constant temperature, e.g., about 2° C. above roomtemperature. This ensures that all cleavage is performed at the sametemperature, regardless of the environmental conditions or level ofusage of the system.

Next, control unit 102 begins to confirm the positioning of containersets 404/406 as well as reading bar codes on both containers. The rotor114 places a container assembly in front of a dispensing station 122.The dispenser head 410 is lowered to make sure that the containerassembly 404/406 is properly mounted on the support frame 402. Ifmounting is improper, the control unit will notify the operator to fixthe problem. As each container set is checked for proper positioning,bar code reader 150 scans each unique bar code on the collectioncontainer and the compound container. (Note that for transferlesscontainers, only one bar code need be scanned.)

After positioning of all the container assemblies has been confirmed andthe bar codes scanned, the dispensing stations 122 are engaged. Thedispensing stations 122 prime the solvent supply system and begindispensing the liquid solutions. Control unit 102 generates a command toincrement rotor 114 to position a container assembly in front of eachdispensing station 122. The dispenser head 122 is lowered to engage theappropriate container assembly. Liquid solution is pumped from sourcecontainers 124 into reservoir chamber 1408 of dispensing station 122.The liquid solution fills to a level above the top of the fill containerin reservoir chamber 1408 and the excess that does not remain in thereservoir wells 1432 is drained back into the source container 124. Ameasured amount of solvent remains in reservoir wells 1432. In theexemplary embodiment, using a mixture of 50% TCA and 50% DCM, 250microliters is retained in each reservoir well 1432.

The dispenser bypass valve 187 is closed and dispenser displacementvalve 185 is opened by commands from control unit 102. Nitrogen ispumped through dispenser displacement valve 185 into reservoir chamber1408. As reservoir chamber 1408 is pressurized, the liquid solution inthe reservoirs 1432 is forced through tubes 414 and dispensed into thecontainer assembly 404/406 that is positioned under the dispensing head410. This procedure continues until all of the desired containerassemblies are filled with liquid solution.

As is known, during cleavage using solvents such as TFA, a phenomenonknown as “creep” can occur, where well vapors can condense on or nearthe upper surface of the wells in the compound container and, over time,move from well-to-well, resulting in cross-contamination of compoundscontained in the wells. To address this problem, after the containerassemblies 404/406 have been filled, rotor 114 is activated to spin thecontainer assemblies at a low rotational speed, e.g., 20-30 r.p.m. Thelow rotational speed acts in a manner similar to air blowing across thetops of the wells, carrying solvent vapors away from a well before theycan condense in other wells.

To provide an example, for procedures using a 50:50 mixture TCA and DCM,after an incubation of about an hour, the rotor will be halted anddispensing station 122′ will be used to dispense 100 microliters perwell into each container assembly 404/406 to top off each sample well tocompensate for solvent that evaporates or is otherwise lost duringincubation. After all sample wells have been filled, rotor 114 is againactivated to spin at low speed, and incubation continues until cleavageis completed, which will be on the order of a few hours. Selection ofappropriate cleavage conditions and duration will depend on the type ofsamples to be cleaved and the type and concentration of solvent. Thoseof skill in the art will be capable of selecting appropriate parametersfor cleavage using the inventive system and method.

When cleavage is complete, chamber 112 is evacuated and the rotor speedis increased to a high rotational speed to start the transfer and/orevaporation process. Vacuum subsystem 140 is engaged and starts runningthe diaphragm pump 146. When the internal pressure of the centrifugechamber 112 reaches about 100 mbar, Roots pump 144 begins to warm up. Atabout 50 mbar, the control unit 102 switches the pump selector valve 141to direct exhaust to Roots pump 144. Roots pump 144 is engaged and itsexhaust is fed into diaphragm pump 146. Diaphragm pump 146 compressesthe vapors and exhausts them to condenser 148 where the vapors arecondensed on coils cooled by water from recirculating chilled water bath188. The remaining vapors are exhausted to the vapor venting system 170and the condensate is drained to waste disposal system 160. This processcontinues until the internal pressure of the centrifuge chamber 112 isequivalent to about 1 mbar.

The rotor speed is increased to a substantially higher speed, preferablyon the order of 800 r.p.m. The centrifugal force of the rotor's spinningcauses the cleavage solution and cleavage compound to be transferredfrom the wells 1710 of compound containers 404 into the wells 2302 ofcollection containers 406. (In processes using the transferlesscontainer assembly 3002, no transfer occurs and this step merely servesas part of the concentration evaporation sequence.) The high rotationalspeed during evaporation also reduces “bumping”. Temperature controlsubsystem 130 heats the heat plates 704 to keep the samples at aconstant temperature and prevent cooling as the solvents evaporate, andthe vacuum subsystem 140 continues to operate to maintain the vacuumwithin chamber 112 as the solvent vapors are released into the chamberatmosphere, thus assisting in evaporation of the solvent. Temperaturecontrol subsystem deactivates chamber heaters 1202 since, under vacuum,heating the chamber 112 has little effect.

As the container assemblies 404/406 pass each window 132, the bottoms ofheat plates 704 are exposed to the infrared light of the heat lamps 138.As the temperature of heat plates 704 changes, the temperature sensor1102 detects the temperature of the heat plates and communicates thatinformation to the infrared transmitter 135. The infrared transmitter135 transmits an infrared signal through window 134 where it is detectedby infrared sensor 136 which then relays the temperature information tothe heat controller. The temperature controller monitors the heat-inputvalue, i.e., the energy input by heat lamps 138 and the heat platetemperature to maintain the samples at a constant temperature, typicallyat or slightly below room temperature. As the volatile solventevaporates, the heat plate temperature decreases due to the coolingeffect of the evaporation. The temperature controller responds to thiscooling by increasing the heat input to the heat plates. By monitoringthe level of heat-input required to maintain the target temperature, itis possible to determine the evaporation rate of the liquid in the wellsand accurately detect the end of the evaporation cycle. When additionalheat is no longer required to compensate for the cooling effect of thesolvent, the solvent evaporation is complete. This improves the overallsystem throughput and avoids the risk of overheating the samplecompounds.

After the solvent in wells 2302 of the collection container 406 (or inwells 3004 of transferless container assembly 3002) has been completelyevaporated, the gas supply subsystem purges centrifuge chamber 112 toremove residual vapors and the rotor drive motor is turned off, allowingthe rotor to slow and eventually stop. Control unit 102 then sends acommand to unlock the hinged lid 116, allowing the operator to openhinged lid 116 and remove the container assemblies 404/406 from thecentrifuge 110. The evaporation cycle where the solvent is TFA or DCM,or a combination of the two, will take on the order of 20 minutes Thisimplementation is only meant to be an example for illustrative purposes.

In a second exemplary implementation, DNA purification is performed byintroducing biological samples, e.g., whole blood, plasma, buffy coat,bone marrow, viral or bacterial suspensions, etc., into wells 3110 ofsample container 3104 of container assembly 3102. Porous glass plugs3118 or other appropriate porous material are placed in the lower endsof cylindrical sections 3112 to prevent solid support material, such asresin or silica frit, from escaping through drain tubes 3108. A secondporous glass plug 3116 can be placed on top of the solid support toprevent material from escaping at the top of well 3110. Containerassembly 3102 is placed on the centrifuge rotor and the centrifugechamber is closed. In an alternate implementation, the columnarrangement can be replaced by using a solid support such as thatillustrated in FIG. 21, i.e., a porous container filled with anappropriate solid support material such as resin or silica frit, forexample, the IRORI NanoKan™ or IRORI MicroKan®. In this latterembodiment, the sample/collection container assembly described and shownin FIGS. 17 and 21-25 can be used for processing of biological samples.

The centrifuge chamber can be evacuated and backfilled to atmospherewith nitrogen to ensure uniform processing conditions. Purificationsolution, e.g., a detergent-containing buffer, is introduced bypositioning each container assembly 3102 under a dispensing station.After each container assembly has received the appropriate amount ofsolution, the rotor is activated and, where appropriate, the temperatureincreased. It may be possible to perform multiple washing steps or otherpurification steps within a centrifuge cycle by introducing a secondsolution or a plurality of second solutions into the container wells.The waste solution is collected in the wells of waste collectioncontainer 3106. After one or more purification steps is completed, thecentrifuge rotor is stopped, the chamber brought back up to atmosphere,and the operator opens the chamber door to access the sample containers.The waste collection container 3106 is removed from each assembly 3102and a clean collection container is assembled with the sample container3104. The assembly is then placed back on the rotor, the chamberevacuated and backfilled, if desired, and elution reagent is dispensedinto each of the container well by one of the dispensing stations. Thechamber can be heated to incubate the samples while centrifugationassists in cleaving the DNA samples from the solid supports. Theremaining steps are similar to those described above for the chemicalcleavage and can be readily adapted by one of skill in the art tocomplete the purification and cleavage of the biological samples.

The cleavage/evaporation/collection system and the method of using thatsystem provide many advantages over devices and methods currently inuse. In particular, the invention provides a highly automated system andmethod for sequentially washing, cleaving, eluting, concentrating,purifying, and/or collecting a large number of chemical compounds orbiological samples in a rapid and cost effective which minimizes thehandling of both the samples themselves and the hazardous chemicals usedin cleavage or other processes. The system is sealed and constructed ofmaterials that are resistant to the corrosive solvents typically used incleavage and purification procedures, providing increased safety, higherthroughput and better control compared to known systems and methods.

It will be apparent to those skilled in the art that variousmodifications and variations may be made in the apparatus and process ofthe present invention without departing from the spirit or scope of theinvention. Thus, it is intended that the present invention cover themodification and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

We claim:
 1. A sample/collection container for automated processing of aplurality of samples on solid supports, the container comprising: aplurality of sample wells, each sample well dimensioned to receive andretain a solid support and to permit a solution to flow past the solidsupport; a plurality of collection wells in a collection containerdisposed to receive and retain solution that flows past the solidsupport, wherein each collection well of the plurality corresponds toone sample well, and wherein the solution removes at least a portion ofthe plurality of samples for collection in the collection wells; and thecollection container having a bottom adapted to conform to a heatingplate for distributing heat to the collection wells wherein the adaptedbottom comprises rounded well bottoms that are slightly recessed fromthe bottom edge of the collection container in order to correspond to aseries of recesses in the heating plate for providing uniform heatdistribution to the collection wells.
 2. The sample/collection containerof claim 1, wherein the plurality of sample wells is disposed within asample container, each sample well having a drain connected thereto,wherein, when centrifugal force is applied to the sample container, thesolution in the sample well is forced into the corresponding drainleaving the solid support in the sample well, and the plurality ofcollection wells are disposed in a collection container so that eachdrain of the sample container is directed to a corresponding collectionwell so that the solution is transferred from the sample well into thecollection well.
 3. The sample/collection container as in claim 1,wherein each of the sample/collection container has 96 wells.
 4. Thesample/collection container of claim 1, wherein the solid supports areselected from the group consisting of loose beads, tubes, pins, crowns,disks, balls, cubes, blocks, and porous containers containing resinparticles or beads.
 5. The sample/collection container of claim 1,wherein each sample well is configured as a column with a plurality ofporous plugs disposed therein for retaining the solid support and abiological sample therebetween.
 6. The sample/collection container ofclaim 1, wherein the sample wells and collection wells are integratedwithin a single container and further comprising a restriction disposedbetween each sample well and its corresponding collection well so thatthe solid support is retained in the sample well while the solution ispermitted to pass through to the collection well.
 7. Thesample/collection container of claim 6, wherein the restrictioncomprises at least one protrusion extending radially into the well forrestricting the inner diameter of the well to prevent the solid supportfrom dropping to the bottom of the well.
 8. The sample/collectioncontainer of claim 7, wherein the at least one protrusion comprises arib, ridge, ring or tab.
 9. A sample/collection container for automatedprocessing of a plurality of samples on solid supports, the containercomprising: a sample container having an array of sample wells formedtherein, each sample well dimensioned to receive a sample on a solidsupport and having a drain connected thereto, wherein, when centrifugalforce is applied to the sample container, a solution in the sample wellis forced into the corresponding drain leaving the solid support in thesample well; a collection container removably attached to a bottom ofthe sample container, the collection container having an array ofcollection wells corresponding to the array of sample wells so that eachdrain of the sample container is directed to a corresponding collectionwell so that the solution is transferred from the sample well into thecollection well; and the collection container having a bottom adapted toconform to a heating plate for distributing heat to the collection wellswherein the adapted bottom comprises rounded well bottoms that areslightly recessed from the bottom edge of the collection container inorder to correspond to a series of recesses in the heating plateproviding uniform heat distribution to the collection wells.
 10. Thesample/collection container as in claim 9, wherein each of thesample/collection container has 96 wells.
 11. The sample/collectioncontainer of claim 9, wherein the solid supports are selected from thegroup consisting of loose beads, tubes, pins, crowns, disks, balls,cubes, blocks, and porous containers containing resin particles orbeads.
 12. The sample/collection container of claim 9, wherein eachsample well is configured as a column with a plurality of porous plugsdisposed therein for retaining the solid support and a biological sampletherebetween.
 13. A sample/collection container for automated processingof samples on solid supports, the container comprising: a plurality ofwells sample, each well having a first inner diameter at an upperportion and a second inner diameter smaller than the first innerdiameter at a lower portion, wherein the second inner diameter issmaller than the solid support so that the solid support is retained inthe well above the lower portion and a collection container having aplurality of collection wells corresponding to the sample wells andhaving a bottom adapted to conform to a heating plate for distributingheat to the collection wells wherein the adapted bottom comprisesrounded well bottoms that are slightly recessed from the bottom edge ofthe collection container in order to correspond to a series of recessesin the heating plate for providing uniform heat distribution to thecollection wells.
 14. The sample/collection container of claim 13,wherein the lower portion comprises at least one protrusion extendingradially into the well for reducing the first inner diameter of the wellto prevent the solid support from dropping to the bottom of the well.15. The sample/collection container of claim 14, wherein the at leastone protrusion comprises a rib, ridge, ring or tab.
 16. Thesample/collection container as in claim 13, wherein each of thesample/collection container has 96 wells.
 17. The sample/collectioncontainer of claim 13, wherein the solid supports are selected from thegroup consisting of loose beads, tubes, pins, crowns, disks, balls,cubes, blocks, and porous containers containing resin particles orbeads.
 18. A sample/collection container for automated processing of aplurality of samples on solid supports, the container comprising: aplurality of sample wells, each sample well dimensioned to receive andretain a solid support and to permit a solution to flow past the solidsupport; and a plurality of bridge portions wherein each bridge portionfunctionally connects one sample well to a corresponding drain tube tofacilitate transport of the solution upward from each sample well,across the bridge portion and through the drain tube into a plurality ofcollection wells disposed to receive and retain solution that flows pastthe solid support, wherein each collection well of the pluralitycorresponds to one sample well, and wherein the solution removes atleast a portion of the plurality of samples for collection in thecollection wells.
 19. The sample/collection container of claim 18,wherein the plurality of sample wells is disposed within a samplecontainer, each sample well having a drain connected thereto, wherein,when centrifugal force is applied to the sample container, the solutionin the sample well is forced into the corresponding drain leaving thesolid support in the sample well, and the plurality of collection wellsare disposed in a collection container so that each drain of the samplecontainer is directed to a corresponding collection well so that thesolution is transferred from the sample well into the collection well.20. The sample/collection container as in claim 18, wherein thecollection well has a bottom adapted to conform to a heating plate fordistributing heat to the collection wells.
 21. The sample/collectioncontainer as in claim 18, wherein each of the sample/collectioncontainer has 96 wells.
 22. The sample/collection container of claim 18,wherein the solid supports are selected from the group consisting ofloose beads, tubes, pins, crowns, disks, balls, cubes, blocks, andporous containers containing resin particles or beads.
 23. Thesample/collection container of claim 18, wherein each sample well isconfigured as a column with a plurality of porous plugs disposed thereinfor retaining the solid support and a biological sample therebetween.24. The sample/collection container of claim 18, wherein the samplewells and collection wells are integrated within a single container andfurther comprising a restriction disposed between each sample well andits corresponding collection well so that the solid support is retainedin the sample well while the solution is permitted to pass through tothe collection well.
 25. The sample/collection container of claim 24,wherein the restriction comprises at least one protrusion extendingradially into the well for restricting the inner diameter of the well toprevent the solid support from dropping to the bottom of the well. 26.The sample/collection container of claim 25, wherein the at least oneprotrusion comprises a rib, ridge, ring or tab.
 27. A sample/collectioncontainer for automated processing of a plurality of samples on solidsupports, the container comprising: a sample container having an arrayof sample wells formed therein, each sample well dimensioned to receivea sample on a solid support and having a bridge portion wherein eachbridge portion functionally connects one sample well to a correspondingdrain tube to facilitate transport of each sample upward from eachsample well, across the bridge portion and through the drain tube and adrain connected thereto, wherein, when centrifugal force is applied tothe sample container, a solution in the sample well is forced into thecorresponding drain leaving the solid support in the sample well; acollection container removably attached to a bottom of the samplecontainer, the collection container having an array of collection wellscorresponding to the array of sample wells so that each drain of thesample container is directed to a corresponding collection well so thatthe solution is transferred from the sample well into the collectionwell.
 28. The sample/collection container as in claim 27, wherein thecollection well has a bottom adapted to conform to a heating plate fordistributing heat to the collection wells.
 29. The sample/collectioncontainer as in claim 27, wherein each of the sample/collectioncontainer has 96 wells.
 30. The sample/collection container of claim 27,wherein the solid supports are selected from the group consisting ofloose beads, tubes, pins, crowns, disks, balls, cubes, blocks, andporous containers containing resin particles or beads.
 31. Thesample/collection container of claim 27, wherein each sample well isconfigured as a column with a plurality of porous plugs disposed thereinfor retaining the solid support and a biological sample therebetween.32. A sample/collection container for automated processing of samples onsolid supports, the container comprising: a plurality of wells, eachwell having a first inner diameter at an upper portion and a secondinner diameter smaller than the first inner diameter at a lower portion,wherein the second inner diameter is smaller than the solid support sothat the solid support is retained in the well above the lower portionand each having a bridge portion wherein each bridge portionfunctionally connects one sample well to a corresponding drain tube tofacilitate transport of samples out of each well, across the bridgeportion and through the drain tube and into a collection well.
 33. Thesample/collection container of claim 32, wherein the lower portioncomprises at least one protrusion extending radially into the well forreducing the first inner diameter of the well to prevent the solidsupport from dropping to the bottom of the well.
 34. Thesample/collection container of claim 33, wherein the at least oneprotrusion comprises a rib, ridge, ring or tab.
 35. Thesample/collection container as in claim 32, wherein the collection wellhas a bottom adapted to conform to a heating plate for distributing heatto the collection wells.
 36. The sample/collection container as in claim32, wherein each of the sample/collection container has 96 wells. 37.The sample/collection container of claim 32, wherein the solid supportsare selected from the group consisting of loose beads, tubes, pins,crowns, disks, balls, cubes, blocks, and porous containers containingresin particles or beads.